Various Degrees Of Renal Impairment Research Articles

Towards optimizing cefepime/tazobactam (WCK 4282) exposure to achieve efficacy against piperacillin/tazobactam-resistant ESBL infections: dose recommendations for various renal functions, including intermittent haemodialysis, in healthy individuals.

WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination. We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required. The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L.

622. Population Pharmacokinetic Analysis and Probability of Target Attainment Simulations of Pivmecillinam for the Treatment of Uncomplicated Urinary Tract Infection

Abstract Background A population pharmacokinetic model was developed to characterize mecillinam (MEC) pharmacokinetics (PK) and urine exposure after intravenous (IV) administration of MEC or after oral (PO) administration of its prodrug pivmecillinam (PIV) in healthy subjects and patients with renal impairment (RI) or infections. MEC is a β-lactam antibiotic with a targeted spectrum of activity against Enterobacterales. The model was used to investigate various PIV treatment regimens and covariate scenarios on plasma exposure and urine excretion, and to perform probability of target attainment (PTA) simulations in support of dose justification for the treatment of uncomplicated urinary tract infection (uUTI). Methods The analysis was based on MEC PK data obtained in plasma, serum, and urine in 15 clinical studies. The dataset included a total of 3964 plasma or serum concentrations and 989 urine samples obtained in 228 subjects. Those 228 subjects consisted of 172 healthy volunteers, 23 patients with infections (uUTI, Gram-negative infection, typhoid, or paratyphoid fever), and 33 patients with various degrees of renal impairment (RI). Subjects were treated with single or multiple doses of MEC (IV, 200-1410 mg) or PIV (PO, 137-500 mg). Results MEC PK profiles in plasma and urine were well characterized by a 2-compartment distribution model with first-order renal elimination and nonlinear non-renal elimination. Oral absorption of PIV was best described using a single (Erlang) transit compartment. The PK model included parameter-covariate relationships for WT on all clearance and volume parameters (with fixed allometric exponents of 0.75 and 1), a nonlinear dose effect on bioavailability, formulation effects on Ka, food effects on both Ka and F1, and effects of renal function on both CL and Km. PTA simulations for the proposed dosing regimen of 200 mg TID predicts up to 70% fT>MIC for the CLSI susceptibility breakpoint of 8 mg/L in 90% of the population for a voiding frequency of 45 min. Conclusion MEC PK was well characterized by a 2-compartment distribution model with first-order renal and nonlinear non-renal elimination. The oral PIV absorption was best described using a single transit compartment. PTA simulations were supportive of a 200 mg TID dosing. Disclosures Anne Laurence Santerre Henriksen, PhD, Shionogi: Contractor|UTILITY therapeutics Ltd: Advisor/Consultant Maxime Lagraauw, PhD, qPharmetra: Employee Marita Prohn, n/a, qPharmetra: Employee Lars Lindbom, PhD, qPharmetra: Employee.

Safety and Pharmacokinetics of Taniborbactam (VNRX-5133) with Cefepime in Subjects with Various Degrees of Renal Impairment.

ABSTRACTTaniborbactam, an investigational β-lactamase inhibitor that is active against both serine- and metallo-β-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam coadministered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.

Effects of Renal Impairment on the Pharmacokinetics of Gefapixant, a P2X3 Receptor Antagonist

Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open-label, single-dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end-stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non-HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87-, 2.79-, and 3.76-fold higher exposure (area under the plasma concentration-time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98-, 4.43-, and 4.74-fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration-time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non-HD conditions. Single-dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations.

Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment.

ABSTRACTTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Pharmacokinetic/Pharmacodynamic Simulations of Cost-Effective Dosage Regimens of Ceftolozane-Tazobactam and Ceftazidime-Avibactam in Patients with Renal Impairment.

The pharmacokinetics of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-avibactam (CEF-AVI) is influenced by renal function. Application of recommended dosages in patients with renal impairment requires the use of fractions of the full dose, as only one dosage is available for both antibiotics. The objective of this study was to evaluate the adequacy of alternative dosage regimens based on the full dose. We performed pharmacokinetic/pharmacodynamic (PK/PD) simulations of recommended and alternative dosage regimens in patients with various degrees of renal impairment by using the Pmetrics program. Alternative regimens included longer dosage interval and prolonged infusions of the full dose for both drugs. Probabilities of target attainment (PTA) were assessed considering PK/PD targets defined for cephalosporins and beta-lactamase inhibitors as well as MIC breakpoints. The risk of overexposure was also assessed. Results showed that alternative dosage regimens based on a full dose of TOL-TAZ and CEF-AVI administered every 12 or 24 h were associated with PTA similar to that of recommended dosages, especially when administered as prolonged infusion. The alternative dosage regimens were not associated with overexposure in most cases. In addition, those regimens could reduce dosing errors, drug cost, and nurse labor. Clinical investigation ovf those alternative dosage regimens would be required before implementation.

Superior Efficacy of Carfilzomib and Dexamethasone (Kd56) Vs Bortezomib and Dexamethasone (Vd) in Multiple Myeloma (MM) Patients with Moderate or Serious Renal Failure: A Subgroup Analysis of the Phase 3 Endeavor Study

Abstract Background: Carfilzomib, a second generation selective proteasome inhibitor, is approved in the United States and other countries for the treatment of relapsed or refractory multiple myeloma (RRMM). In the randomized, phase 3 study ENDEAVOR, Kd56 demonstrated clinically and statistically significant improvement compared with Vd in both progression-free survival (PFS) (median 18.7 vs 9.4 months [mos]; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.44-0.65; 1-sided P Methods: Adults with RRMM (1-3 prior regimens) and creatinine clearance (CrCL) ≥15 mL/min were eligible for the ENDEAVOR trial. The Cockcroft-Gault formula was used to calculate baseline, and on study, renal function. In the Kd56 arm, pts received carfilzomib (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. Pts in the Vd arm received bortezomib (1.3 mg/m2; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Pts were treated until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or mortality. The primary end point was PFS; secondary end points included OS, overall response rate (ORR), duration of response, rate of grade ≥2 peripheral neuropathy (PN), and safety. The present analyses examined efficacy and safety outcomes in pts grouped according to baseline renal function (CrCL ≥15 to Results: A total of 929 pts were enrolled (CrCL ≥15 to Conclusions: To our knowledge, ENDEAVOR is the largest randomized trial in RRMM to have included pts with severe renal impairment. Superior efficacy for Kd56 vs Vd was observed across all renal subgroups. The safety profile was consistent with the findings from the previous interim analysis. Overall, these data suggest that Kd56 has a favorable benefit-risk profile and should be considered as the new standard of care in pts with RRMM, regardless of baseline renal function. Download : Download high-res image (203KB) Download : Download full-size image Disclosures Dimopoulos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. White: Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Celgene, Janssen, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccia: Pfizer Inc., Sandoz: Other: Advisory Board. Yang: Amgen Inc.: Employment, Equity Ownership. Kimball: Amgen: Employment, Equity Ownership. Iskander: Amgen: Employment, Equity Ownership. Mezzi: Amgen, Inc.: Employment, Equity Ownership. Ludwig: Janssen-Cilag: Consultancy, Speakers Bureau; Bristol-Meyers: Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Niesvizky: Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy.

Using an Enhanced Electronic Heath Record to Analyze Treatment Patterns and Clinical Characteristics in Patients with Relapsed or Refractory Multiple Myeloma Receiving Pomalidomide

INTRODUCTIONRecent approvals in multiple myeloma (MM) treatment have focused on addressing unmet needs among patients who have failed prior therapies. Pomalidomide (POM) is an IMiD® immunomodulatory agent approved in the United States (US) by the US Food and Drug Administration in 2013 in combination with low-dose dexamethasone (Dex) for patients with MM who have received ≥ 2 prior therapies including lenalidomide and a protease inhibitor in relapsed or refractory multiple myeloma (RRMM). Due to the relatively small population with RRMM and the inherent limitations of most observational research databases, no previous study has described the real-world patterns of using POM in RRMM in the US. The purpose of this analysis was to describe the clinical characteristics, treatment patterns, and regimen sequencing of patients who received POM in a US practice setting using an enhanced electronic health records (EHR) database containing over 6000 patients with MM across the US.METHODSThis retrospective observational study identified patients with MM (ICD-9: 203.0x or ICD-10: C90.xx) between 01/01/2011 and 05/31/2017 in the Flatiron Health electronic records database. Diagnosis of MM was confirmed through review of unstructured chart data (eg, physician notes in the EHR). The Flatiron MM provider network comprises over 265 clinics throughout the US. Patients were included if they received POM in any line of therapy and were not enrolled in a clinical trial. Patients were further categorized into 2 subgroups: POM in second-line therapy (POM 2L) or POM in third-line therapy (POM 3L). Demographic and clinical characteristics were described at baseline. Laboratory values were obtained from structured fields and were reported if available within 60 days of the date of POM therapy initiation. Regimens received in the line prior to and post-POM use were described, as was the patient disposition at the end of the study period.RESULTSFor the 572 pomalidomide patients (ALL POM) identified, mean (SD) age was 67.2 (10.5) years at the time of first exposure to POM, 50.2% were female, 61.7% white, 14.7% African American, and 23.6% other/unknown races. In the ALL POM population with available laboratory values, 457 (99.1%) had serum calcium levels of < 11 mg/dL. Of the 373 ALL POM patients with available estimated glomerular filtration rate (eGFR) data, baseline values were > 60 mL/min in 212 (56.8%), 30-60 mL/min in 115 (30.8%), < 30 mL/min with no dialysis in 37 (9.9%), and < 30 mL/min with dialysis in 9 (2.4%). In those with available International Staging System data (n = 169), 27.8% were stage I, 33.7% were stage II, and 38.5% were stage III. There were 126 patients (22.0%) who received POM 2L and 115 (20.1%) received POM 3L. Clinical characteristics were similar across subgroups, except M-Spike and free light chain ratio were higher in POM 3L. The most common POM-based regimens received in 2L were POM-Dex (POM-d; 40 [31.8%]), followed by POM-carfilzomib-Dex (PKd; 33 [26.2%]); the most common in 3L were POM-d (47 [40.9%]) and PKd (19 [16.5%]). Lenalidomide in the immediate prior line of therapy was received by 88.1% of POM 2L and 66.1% of POM 3L. In the POM 3L group, 90.4% of patients received lenalidomide in any prior line of therapy. Most patients in POM 2L received lenalidomide, bortezomib, and Dex (RVd) 1L (79 [62.7%]). Of the 126 patients in POM 2L, 39.1% received POM in any subsequent line and 49.2% were categorized as receiving no post-treatment for the following reasons: 28.6% were lost to follow-up, 7.9% were in a treatment gap (defined as a gap of > 180 days), 7.9% had died, and 4.8% were still in POM 2L treatment at the end of the study (Figure 1). Of the 115 patients in POM 3L, 34.0% received POM in any subsequent line and 53.9% were categorized as receiving no post-treatment: 16.5% were lost to follow-up, 10.4% were in a treatment gap, 24.4% had died, and 2.6% were still in POM 3L treatment at the end of the study.CONCLUSIONSData from an enhanced EHR database showed that most patients who received POM in 2L or 3L treatment were exposed to lenalidomide in prior therapy. The clinical characteristics (serum calcium levels and eGFR) of POM patients also suggest that POM was used in patients with various degrees of renal impairment. With a longer follow-up time, we will be able to observe treatment patterns in later lines of therapy and determine the value newer agents have in the management of patients with MM. [Display omitted] DisclosuresClancy:Celgene Corporation: Employment. Mouro:Celgene Corporation: Employment, Equity Ownership. Tian:Celgene: Employment. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau.

The Pharmacology, Efficacy, and Safety of Rivaroxaban in Renally Impaired Patient Populations.

Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real‐world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.

An open-label, pharmacokinetic study of lenalidomide and dexamethasone therapy in previously untreated multiple myeloma (MM) patients with various degrees of renal impairment – validation of official dosing guidelines

Lenalidomide is a backbone agent in the treatment of multiple myeloma, but dose adjustment is required for those with renal impairment (RI). We evaluated the pharmacokinetics (PK) and safety of lenalidomide and dexamethasone as frontline pre-transplant induction, with doses adjusted at start of each cycle based on creatinine clearance, as per the official dosing guidelines. After 4 cycles, PK studies showed that patients with moderate RI (30 ≤ CrCl < 60 mL/min) receiving 10 mg dosing may be under-dosed and those with severe RI (CrCl <30ml/min) appeared appropriately dosed initially, but sustained significant decreases in maximum serum concentration (Cmax) after repeated dosing, due to rapid clinical improvement and enhanced drug clearance. PK drug monitoring during cycle 1 may facilitate appropriate and timely dose adjustments. Adverse events rates did not vary based on severity of RI. No patient discontinued lenalidomide for toxicity. This supports the feasibility and safety of frontline lenalidomide in transplant-eligible patients with RI.

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Pramipexole Pharmacokinetics in Parkinson's Disease Patients With Renal Impairment.

Pramipexole is the first-line medication recommended by the British National Institute for Health and Care Excellence. Pramipexole is predominantly eliminated by renal excretion. The aim was to develop a physiologically based pharmacokinetic (PBPK) model of pramipexole, providing a basis for its individualized administration. The role of glomerular filtration and organic cation transporter 2 (OCT2) in renal tubular secretion was considered. Plasma concentration-time profiles of pramipexole were predicted and validated, first in healthy populations and then in PD patients with varied renal function. Finally, the pharmacokinetics of PD patients with different degrees of renal impairment were predicted. The simulated pharmacokinetic parameters, including maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (tmax ), and steady-state trough plasma concentration values, obtained using the PBPK model were validated using fold error values, which were all smaller than 2. The successfully validated model supported that OCT2-mediated tubular secretion was affected proportionally to changes in glomerular filtration for various degrees of renal impairment. The predicted AUC0-inf values were increased 1.16-, 1.76-, 3.26-, and 9.48-fold in mild, moderate, and severe renal impairment and end-stage renal disease (ESRD) subjects, resepctively, compared with PD patients with normal renal function. It appears that PD patients with mild renal impairment are unlikely to require dose adjustment (0.125 mg 3 times a day). The pramipexole dose should be reduced to approximately 0.125 mg twice daily, 0.125 mg once daily, and 0.0375 mg once daily in PD patients with moderate renal impairment, severe renal impairment, and ESRD, respectively.

Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects.

Sulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics and safety profile of durlobactam (also known as ETX2514) and sulbactam after single intravenous (i.v.) dose administration. For healthy subjects and those with mild or moderate renal impairment (RI), single 1,000-mg doses each of durlobactam and sulbactam via a 3-h i.v. infusion were administered, and for severe renal impairment, 500-mg doses were administered. For subjects with ESRD and HD, 500-mg i.v. doses each of durlobactam and sulbactam were administered post-HD and pre-HD, with a 1-week washout between doses. Among 34 subjects, decreasing renal function increased systemic exposure (peak plasma concentration [Cmax] and area under the concentration-time curve [AUC]) to durlobactam and sulbactam in a generally linear manner. In healthy subjects and in those with mild or moderate renal impairment, the majority of durlobactam and sulbactam was excreted in the urine, while approximately 40% or less was excreted in urine in subjects with severe renal impairment or ESRD. In subjects with ESRD, hemodialysis was effective at removing both durlobactam and sulbactam from plasma. Renal impairment had no effect of the safety/tolerability profile of durlobactam and sulbactam. In summary, RI and ESRD had a predictable effect on the pharmacokinetic (PK) profile of durlobactam and sulbactam with no adverse effects on the safety/tolerability profile. Durlobactam and sulbactam are cleared to a similar extent by renal elimination and are impacted similarly by renal impairment. The results from this study have been used with population PK modeling and nonclinically derived PK/PD (pharmacodynamic) exposure targets to establish dosage recommendations for durlobactam and sulbactam in patients with various degrees of RI. The dosing regimen of durlobactam-sulbactam will require adjustment in patients with severe renal insufficiency and in those with ESRD.

The Current Practice of Opioid for Cancer Dyspnea: The Result From the Nationwide Survey of Japanese Palliative Care Physicians

ContextMorphine is recommended as the first-line pharmacological therapy for cancer dyspnea. However, the detailed practice of morphine has not been evaluated and consensus about other opioids for cancer dyspnea has not been established. ObjectivesTo explore the physician-reported practice of opioid for cancer dyspnea. MethodsA nationwide mail-questionnaire survey was conducted among 536 Japanese certified palliative care physicians. We randomly selected 268 and asked the following: 1) how the physicians themselves initiate and use morphine for cancer dyspnea, 2) opioid choice for dyspnea in patients who have already used opioid other than morphine regularly, and 3) opioid choice for dyspnea in patients with various degrees of renal impairment in their daily practice. ResultsOverall, 192 physicians responded (response rate, 71.6%). The major (58.3%) practice of initiating morphine was “immediate-release morphine as needed” in opioid-naïve patients, and the mean % increase when they titrate morphine for cancer dyspnea was 29.4 ± 11.3% of the baseline dose. Although “titrate baseline oxycodone” was the most frequent (42.3%) for low-to-moderate–dose regular oxycodone cases, “stepwise switch to morphine” (30.0%) and “add morphine on baseline oxycodone” (27.1%) were the more frequent practices for high-dose regular oxycodone. Regardless of the baseline dose, “add morphine on baseline fentanyl” was the most frequent practice for regular transdermal fentanyl cases. Oxycodone was the most frequent choice in renal insufficiency cases, regardless of its degree. ConclusionsAmong Japanese palliative care physicians, using oxycodone for cancer dyspnea was relatively popular practice, whereas fentanyl was not. Oxycodone was the most preferred opioid for cancer dyspnea in the setting of renal insufficiency among Japanese palliative care physicians. We should conduct studies to confirm the safety and effectiveness of these opioid practices for cancer dyspnea.

Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure.

BackgroundCurrent therapies for anemia of chronic kidney disease (CKD) include administration of supplemental iron (intravenous and/or oral), blood transfusions and replacement of erythropoietin through the administration of recombinant human erythropoietin (rhEPO) and rhEPO analogs, each with limitations. Daprodustat is an orally active, small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently in Phase 3 clinical studies. As it is well appreciated that the kidney represents a major route of elimination of many drugs, and daprodustat will be administered to patients with advanced CKD as well as patients with end-stage kidney disease, it is important to characterize the pharmacokinetic profile in these patient populations to safely dose this potential new medicine.Methods The primary objective of these studies, conducted under two separate protocols and with identical assessments and procedures, was to characterize the steady-state pharmacokinetics of daprodustat and the six predominant metabolites (i.e. metabolites present in the highest concentration in circulation) in subjects with normal renal function, anemic non-dialysis (ND)-dependent CKD subjects (CKD Stage 3/4) and anemic subjects on either hemodialysis (HD) or peritoneal dialysis (PD). All enrolled subjects were administered daprodustat 5 mg once daily for 14 days (all except HD subjects) or 15 days (for HD subjects). Blood, urine and peritoneal dialysate were collected at various times for measurement of daprodustat, predominant metabolite, erythropoietin and hepcidin levels.Results The pharmacokinetic properties of steady-state daprodustat peak plasma concentration (Cmax), area under the plasma daprodustat concentration-time curve (AUC) and the time of Cmax (tmax) were comparable between all cohorts in this study. In addition, there was no clinically relevant difference in these properties in the HD subjects between a dialysis and ND day. For CKD Stage 3/4, HD (dialysis day) and PD subjects, the AUC of all daprodustat metabolites assessed was higher, while the Cmax was slightly higher than that in subjects with normal renal function. Over the course of the 14 or 15 days of daprodustat administration, hemoglobin levels were seen to be relatively stable in the subjects with normal renal function, CKD Stage 3/4 and PD subjects, while HD subjects had a decrease of 1.9 gm/dL. All renally impaired subjects appeared to have similar erythropoietin responses to daprodustat, with approximately a 3-fold increase in these levels. In subjects with minimal to no change in hemoglobin levels, hepcidin levels remained relatively stable. Daprodustat, administered 5 mg once daily for 14–15 days, was generally well tolerated with a safety profile consistent with this patient population.Conclusion These studies demonstrated no clinically meaningful change in the pharmacokinetic properties of daprodustat when administered to subjects with various degrees of renal impairment, while for CKD Stage 3/4, HD (dialysis day) and PD subjects, the Cmax and AUC of all daprodustat metabolites assessed were higher than in subjects with normal renal function. Administration of daprodustat in this study appeared to be generally safe and well tolerated.

Urinary neutrophil gelatinase-associated lipocalin as a clinical biomarker in patients with diabetic nephropathy in Beni-Suef Governorate, Egypt

Aim To demonstrate the importance of the marker of tubulointerstitial damage, urinary neutrophil gelatinase-associated lipocalin (uNGAL), in the follow-up of the progression of chronic kidney disease in patients with type 2 diabetes mellitus. Patients and methods A total of 60 patients with type 2 diabetes mellitus with various degrees of renal impairment were subdivided into three categories based on urine albumin/creatinine ratio (UACR): 20 patients with normoalbuminuria ( 300 mg albumin/g Cr). Few exclusion criteria were considered such as infections, neoplasia, and any inflammation that could interfere with uNGAL measurement. Twenty healthy individuals were taken as a control group. Serum creatinine, UACR, urine protein, and estimated glomerular filtration rate (eGFR) are measured to determine their correlation with uNGAL, which was measured using a suitable human NGAL ELISA kit. The Modification of Diet in Renal Disease formula was used to calculate the eGFR in patients. Results The differences between the means of uNGAL in the different patients’ groups were found to be highly statistically significant (P Conclusion NGAL may be useful as a clinical marker to predict and assess the progression of diabetic nephropathy in patients with type 2 diabetes mellitus with nephropathy.

Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment.

The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients treated with conventional medical and dietetic therapy.

This longitudinal prospective observational type study was conceived with the aim to examine the impact on renal resistive index (RRI) of the variables that we can manipulate with therapeutic and or dietetic interventions in a chronic kidney disease population in order to known which of these variables was statistically related to changes in RRI and therefore could become the object of the greatest therapeutic effort. This study was undertaken between May 2016 to May 2017 in the outpatient nephrology and urology clinic of San Donato Hospital in Arezzo. The study population (84 patients: 47 males and 37 females) was randomly selected among the chronic kidney patients (with various degrees of renal impairment) affected by hypertension and or diabetes mellitus. After a comprehensive medical examination these patients were submitted to determination of serum creatinine, glycated hemoglobin, 24-hour urinary albumin excretion and finally renal Doppler ultrasonography. Then the patients were submitted to a full therapeutic and dietetic intervention to ameliorate the renal impairment by a wide range of actions and after on average a one-year interval were submitted again to a new medical examination and a second determination of serum creatinine, glycated hemoglobin, 24-hour urinary albumin excretion and a new renal Doppler ultrasonography too. The comparison between basal and final data revealed a slight reduction in the mean of bilateral renal resistance indices (Delta RRI: -0.0182 ± 0.08), associated to a slight increase in the mean glomerular filtration rate (Delta GFR: 0.8738 ± 10.95 ml/min/1.73 m2), a reduction in mean body weight (Delta weight: -1.9548 ± 5.26 Kg) and mean BMI (Delta BMI: -0.7643 ± 2.10 Kg/m2) as well as a reduction in the mean systolic blood pressure (Delta systolic blood pressure: -8.8333 ± 25.19 mmHg). Statistical analysis showed statistically significant correlations (p < 0.05) between Delta RRI and Delta weight (p < 0.03), Delta BMI (p < 0.02) and Delta systolic blood pressure (p < 0.05). Despite the many limitations the our study clearly identifies the targets (yet widely known) to act on to prevent kidney alterations related to RRI and provides further evidence, if any, of the utility of RRI as a key parameter in monitoring patients with chronic renal failure and as a valuable tool to drive the clinical efforts to contrast the kidney disease.

Single-dose linezolid pharmacokinetics in critically ill patients with impaired renal function especially chronic hemodialysis patients.

Renal failure patients were treated with linezolid (LZD) for proven or suspected infections by multi-resistant Gram-positive cocci. The aim of this study was to determine if dose adjustment of LZD is needed as a function of renal impairment or not, especially that a significant component of LZD is eliminated unchanged in urine. The single dose pharmacokinetics of LZD was investigated. Eighteen non-infected male subjects with various degrees of renal impairment ranged from normal to severe chronic impairment were enrolled, including end-stage renal disease (ESRD) patients maintained on hemodialysis (HD). LZD was administered as a single oral 600 mg dose, and blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. A similar rate and extent of LZD absorption and elimination and comparable body exposure was observed in both healthy subjects and acute renal failure patients. The extent of LZD exposure was significantly increased by 3-fold in ESRD patients in their off-dialysis day. Furthermore, the t1/2 and MRT values were significantly increased by ~5- and 3-fold, respectively. The Vd /F values of LZD did not change with renal function. A significant decrease in CL/F by ~3-fold was observed in ESRD patients in their off-dialysis day however, CL/F was significantly increased by ~4-fold during HD. Approximately half of the administered LZD dose was removed during the HD session in these selected cohorts of ESRD patients. LZD was generally well tolerated. The dose of LZD did not need to be adjusted for patients with acute renal dysfunction or ESRD on HD. One of the twice-daily doses should be administered after the dialysis session because almost half of the LZD dose was substantially removed by HD. During the first three dialysis sessions of the treatment course, to avoid potentially ineffective therapy, a supplemental dose of LZD might be given if necessary or the dose of LZD should be administered 4 h before the beginning of the HD session. This was to keep LZD levels above the MIC for the organism causing the infection being treated.

Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

Development of software for data analysis by therapeutic drug monitoring of teicoplanin, a glycopeptide antibiotic

We developed a new software named TEICTDM based on the Bayesian estimation utilized in the therapeutic drug monitoring (TDM) of teicoplanin, a glycopeptide antibiotic, for the estimation of individual pharmacokinetic parameters. Therefore, it is necessary to input more than one plasma concentration(s) determined in individual patient. Individual pharmacokinetic parameters were calculated by a least squares methods, MULTI2 (BAYES). Two-compartment model was applied to determine individual pharmacokinetic parameters in male healthy volunteers in Japan, and the relationship between clearance of teicoplanin and creatinine clearance in adult patients with various degrees of renal impairment in Europe was used. A series of work from data input to graph drawing or printing of results could efficiently carried out with the best of use of this software, suggesting that this software is now available in clinical practice.